US5587451AExpiredUtilityPatentIndex 92

Process for preparing polyazamacrocycles

Assignee: DOW CHEMICAL COPriority: Nov 26, 1993Filed: Oct 7, 1994Granted: Dec 24, 1996

Est. expiryNov 26, 2013(expired)· nominal 20-yr term from priority

Inventors:ATHEY PHILLIP S KIEFER GARRY E

C07D 231/12C07D 249/08C07D 257/02C08G 73/06C07D 233/56C07D 487/14C07D 487/08C08G 73/00

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Claims

Abstract

A process for preparing polyazamacrocyclic compounds using a nucleophilic imidazoline with (A) an ethylene oxide or an ethylene carbonate, in an aprotic solvent, followed by intramolecular amination, and then either basic or acidic hydrolysis; or (B) an electrophilic substrate, in a polar solvent, optionally in the presence of a non-nucleophilic base, to form an intermediate, followed by basic hydrolysis; or (C) a electrophilic substrate, in a polar solvent, optionally in the presence of a non-nucleophilic base, followed by prolonged heating in a polar solvent or by treatment with a peroxide solution, followed by basic hydrolysis to form a urea, then basic hydrolysis under pressure; and separating the desired polyazamacrocycle. The compounds so prepared are useful in pharmaceutical applications.

Claims

exact text as granted — not AI-modified

What is claimed is: 
     
       1. A process for preparing polyazamacrocycle compounds of the formula ##STR46## wherein: each n is independently 2 or 3; m is 0 or an integer from 1 to 3;   s is 0 or 1;   y is 0 or 1;   z is 0 or 1; with the proviso that at least 2 of s, y, and z must be 1;     Q is --CH 2  --, --C(O)-- or --CHR;   R is hydrogen, C 1  -C 6  alkyl, --CO 2  H, --CO 2  (C 1  -C 6  alkyl) or phenyl;   R 1  is hydrogen, --CO 2  H, --CO 2  (C 1  -C 6  alkyl), C 1  -C 6  alkyl, C 1  -C 6  alkyl substituted by NH 2 , NO 2 , isothiocyanato, semicarbazido, thiosemicarbazido, maleimido, bromoacetamido or OR 2 , phenyl or phenyl substituted by NH 2 , NO 2 , isothiocyanato, semicarbazido, thiosemicarbazido, maleimido, bromoacetamido or OR 2  ; or   R and R 1  can be taken together to form a phenyl or phenyl substituted by NH 2 , NO 2 , isothiocyanato, semicarbazido, thiosemicarbazido, maleimido, bromoacetamido or OR 2  ; and   R 2  is hydrogen or C 1  -C 4  alkyl;   which comprises reacting an alkylenepolyamine with a formyl equivalent, either neat or in a nonaqueous solvent, to form the unsubstituted imidazoline of the formula ##STR47## wherein q is independently 2 or 3;   p is 0 or 1;   t is 0, 1 or 2; and   followed by reacting (9) with: (A) 1 equivalent of an ethylene oxide or an ethylene carbonate, in an aprotic solvent, to form an alcohol (16) of the formula ##STR48## wherein Q, s, R and R 1  are defined as for Formula (I) and the dotted line represents the optional presence of a bond; when the bond is present, then t is 0, q is 2 to 3, and p is 1; when the bond is absent, then when t is 0, q is 4 or more and p is 1, when t is 1 or more, q is 2 or more and p is 1;     followed by intramolecular amination to yield (17) of the formula ##STR49## wherein the various terms are defined as for (16) and X is an anion, e.g., a halide ion;   and then either basic or acidic hydrolysis to form a compound of Formula (I); or   (B) an electrophlic substrate, in a polar solvent, optionally in the presence of a non-nucleophilic base, to form a salt (17)) of the formula ##STR50## wherein Q, s, R and R 1  are defined as for Formula (I), X is an anion, and the dotted line represents the presence of a bond, t is 0, q is 2 to 3, and p is 1;   and then basic hydrolysis to form a compound of Formula (I); or   and then basic hydrolysis to form a compound of Formula (I); or   (C) an electrophlic substrate, in a polar solvent, optionally in the presence of a non-nucleophilic base, to form (17) of the formula ##STR51## wherein Q, s, R and R 1  are defined as for Formula (I), X is an anion, and the dotted line represents the presence of a bond, t is 0, q is 2 to 3, and p is 1;   followed by prolonged heating in a polar solvent or by treatent with a peroxide solution to form (18) of the formula ##STR52## wherein Q, s, R and R 1  are defined as for Formula (I) and the dotted lines represent the presence of a double bond, t is 0, q is 2 to 3, and p is 1;   followed by basic hydrolysis to form the urea (19) of the formula ##STR53## wherein Q, s, R and R 1  are defined as for Formula (I) and t is 0, q is 2 to 3, and p is 1;   then basic hydrolysis under pressure to form a compound of Formula (I); and   separating the desired polyazamacrocycle.   
     
     
       2. The process of claim 1 wherein the unsubstituted imidazoline of formula (9) has p is 1, q is 2, and t is 0, which is formula (9a). 
     
     
       3. The process of claim 1, Step (A), wherein the unsubstituted imidazoline of formula (9) has p is 1, q is 2, and t is 0, and the alcohol formed is a compound of the formula ##STR54## where R and R 1  are hydrogen, and the intramolecular amination formed a compound of the formula ##STR55## where R and R 1  are hydrogen X is OH or halogen. 
     
     
       4. The process of claim 1, Step (B), wherein the unsubstituted imidazoline of formula (9) has p is 1, q is 2, and t is 0, and the salt formed is a compound of the formula ##STR56## where R and R 1  are defined as above, and X is OH or halogen, and the resulting product of Formula (I) is a compound of formula (6). 
     
     
       5. The process of claim 1, Step A, wherein the aprotic solvent is dimethylformamide or diglyme. 
     
     
       6. The process of claim 1, Step A, wherein the reaction is done at from about 100° to about 200° C. 
     
     
       7. The process of claim 1, Step A or B, wherein the basic hydrolysis is done with aqueous sodium hydroxide at a temperature from about 25° to about 200° C. 
     
     
       8. The process of claim 1 wherein the imidazole is 1,1&#39;-(1,2-ethanediyl)-bis[4,5-dihydro-1H]-imidazoline. 
     
     
       9. The process of claim 1 wherein the imidazole is 1,2-ethanyl-2-[4,5-dihydro-1H]-imidazoline. 
     
     
       10. The process of claim 1 wherein the electrophilic substrate is 1,2-dibromoethane, 1,2-dichlorethane or tosylates, mesylates, or triflates of ethylene glycol. 
     
     
       11. The process of claim 1 wherein the electrophilic substrate is ethylene oxide, the imidazole is 1,1&#39;-(1,2-ethanediyl)-bis[4,5-dihydro-1H]-imidazoline and product prepared is ##STR57## 
     
     
       12. The process of claim 1 wherein the electrophilic substrate is 1,2-dibromoethane, the imidazole is 1,1&#39;-(1,2-ethanediyl)-bis[4,5-dihydro-1H]-imidazoline, and the product prepared is 1,4,7,10-tetrazacyclododecane. 
     
     
       13. The process of claim 12 wherein the non-aqueous solvent is toluene, diglyme, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, n-propanol, acetonitrile, isopropanol, t-butanol or acetone. 
     
     
       14. The process of claim 1 wherein the electrophilic substrate is 1,2-dibromoethane or 1,2-dichlorethane, or tosylates, mesylates or triflates of ethylene glycol, the imidazole is derived from diethylenetriamine, and the product prepared is triazamacrocyclo-1,4,7-triazacyclononane. 
     
     
       15. The process of claim 1 wherein the electrophilic substrate is 2,3-dibromosuccinic acid, the imidazoline is ##STR58## and the product prepared is 2,3-dicarboxyltetraazacyclododecane. 
     
     
       16. A process for preparing a compound of the formula ##STR59## which comprises reacting an imidazoline of formula (9a) ##STR60## with an electrophlic substrate, in a polar solvent, at an elevated temperature, optionally in the presence of a non-nucleophilic base, to form a compound of the formula ##STR61## where R and R 1  are defined as in claim 1, X is OH or halogen, followed by prolonged heating in a polar solvent or by treatment with a peroxide solution to form a compound of the formula ##STR62## where R and R 1  are defined as in claim 1, followed by basic hydrolysis to form a urea of the formula ##STR63## where R and R 1  are defined as in claim 1, and then basic hydrolysis under pressure to form a compound of formula (6); and separating the desired polyazamacrocycle.   
     
     
       17. The process of claim 16, wherein the polar solvent is dimethylformamide, ethylene gylcol dimethyl ether, dimethylsulfoxide, acetonitrile, isopropanol, n-propanol, t-butanol or diglyme. 
     
     
       18. The process of claim 16, wherein the temperature is from about 60° to about 160° C. 
     
     
       19. The process of claim 16, wherein the basic hydrolysis or basic hydrolysis under pressure is done with aqueous sodium hydroxide at a temperature from about 100° to about 200° C. 
     
     
       20. The process of claim 1, Step (B), wherein the electrophilic substrate is 1,2-dibromoethane, which is reacted with an imadizoline (10) of the formula ##STR64## followed by basic hydrolysis, to yield a 1,4,7-triazacyclononane (22) of the formula ##STR65##  which is a compound of Formula (I). 
     
     
       21. The process of claim 1, wherein the electrophilic substrate is 1,3-dichloroacetone, which is reacted with an imadizoline (9) where p equal to 1, q equal to 2, and t equal 0 to yield a cyclic ketone (25) of the formula ##STR66## where X is OH or halogen followed by basic hydrolysis to yield (26) of the formula ##STR67##  which is a compound of Formula (I). 
     
     
       22. A compound having the formula: ##STR68## 
     
     
       23. A compound having the formula: ##STR69## 
     
     
       24. A compound having the formula: ##STR70## where X is OH or halogen. 
     
     
       25. A compound having the formula: ##STR71## where X is OH or halogen. 
     
     
       26. A compound having the formula: ##STR72## 
     
     
       27. A compound having the formula: ##STR73## 
     
     
       28. A compound having the formula: ##STR74## 
     
     
       29. A compound having the formula: ##STR75## where X is OH or halogen. 
     
     
       30. A compound having the formula: ##STR76##

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